Imaging spatial transcriptomics reveals molecular patterns of vulnerability to pathology in a transgenic α-synucleinopathy model

In Parkinson’s disease and dementia with Lewy bodies, aggregated and phosphorylated α-synuclein pathology appears in select neurons throughout cortical and subcortical regions, but little is currently known about why certain populations are selectively vulnerable. Here, using imaging spatial transcriptomics (IST) coupled with downstream immunofluorescence for α-synuclein phosphorylated at Ser129 (pSyn) in the same tissue sections, we identified neuronal subtypes in the cortex and hippocampus of transgenic human α-synuclein-overexpressing mice that preferentially developed pSyn pathology. Additionally, we investigated the transcriptional underpinnings of this vulnerability, pointing to expression of Plk2 , which phosphorylates α-synuclein at Ser129, and human SNCA ( hSNCA ), as key to pSyn pathology development. Finally, we performed differential expression analysis, revealing gene expression changes broadly downstream of hSNCA overexpression, as well as pSyn-dependent alterations in mitochondrial and endolysosomal genes. Overall, this study yields new insights into the formation of α-synuclein pathology and its downstream effects in a synucleinopathy mouse model.